Select Small Core Structure Carbamates Exhibit High Contact Toxicity to "Carbamate-Resistant" Strain Malaria Mosquitoes, Anopheles gambiae (Akron)

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dc.contributor.authorWong, Dawn M.en
dc.contributor.authorLi, Jianyongen
dc.contributor.authorChen, Qiao-Hongen
dc.contributor.authorHan, Qianen
dc.contributor.authorMutunga, James M.en
dc.contributor.authorWysinski, Aniaen
dc.contributor.authorAnderson, Troy D.en
dc.contributor.authorDing, Haizhenen
dc.contributor.authorCarpenetti, Tiffany L.en
dc.contributor.authorVerma, Asthaen
dc.contributor.authorIslam, Rafiqueen
dc.contributor.authorPaulson, Sally L.en
dc.contributor.authorLam, Polo Chun Hungen
dc.contributor.authorTotrov, Maxim M.en
dc.contributor.authorBloomquist, Jeffrey R.en
dc.contributor.authorCarlier, Paul R.en
dc.contributor.departmentBiochemistryen
dc.contributor.departmentChemistryen
dc.contributor.departmentEntomologyen
dc.date.accessioned2018-10-25T15:28:20Zen
dc.date.available2018-10-25T15:28:20Zen
dc.date.issued2012-10-01en
dc.description.abstractAcetylcholinesterase (AChE) is a proven target for control of the malaria mosquito (Anopheles gambiae). Unfortunately, a single amino acid mutation (G119S) in An. gambiae AChE-1 (AgAChE) confers resistance to the AChE inhibitors currently approved by the World Health Organization for indoor residual spraying. In this report, we describe several carbamate inhibitors that potently inhibit G119S AgAChE and that are contact-toxic to carbamate-resistant An. gambiae. PCR-RFLP analysis was used to confirm that carbamate-susceptible G3 and carbamate-resistant Akron strains of An. gambiae carry wild-type (WT) and G119S AChE, respectively. G119S AgAChE was expressed and purified for the first time, and was shown to have only 3% of the turnover number (kcat) of the WT enzyme. Twelve carbamates were then assayed for inhibition of these enzymes. High resistance ratios (>2,500-fold) were observed for carbamates bearing a benzene ring core, consistent with the carbamate-resistant phenotype of the G119S enzyme. Interestingly, resistance ratios for two oxime methylcarbamates, and for five pyrazol-4-yl methylcarbamates were found to be much lower (4- to 65-fold). The toxicities of these carbamates to live G3 and Akron strain An. gambiae were determined. As expected from the enzyme resistance ratios, carbamates bearing a benzene ring core showed low toxicity to Akron strain An. gambiae (LC50>5,000 μg/mL). However, one oxime methylcarbamate (aldicarb) and five pyrazol-4-yl methylcarbamates (4a–e) showed good to excellent toxicity to the Akron strain (LC50 = 32–650 μg/mL). These results suggest that appropriately functionalized “small-core” carbamates could function as a resistance-breaking anticholinesterase insecticides against the malaria mosquito.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0046712en
dc.identifier.eissn1932-6203en
dc.identifier.issue10en
dc.identifier.othere46712en
dc.identifier.pmid23049714en
dc.identifier.urihttp://hdl.handle.net/10919/85511en
dc.identifier.volume7en
dc.language.isoenen
dc.publisherPLOSen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleSelect Small Core Structure Carbamates Exhibit High Contact Toxicity to "Carbamate-Resistant" Strain Malaria Mosquitoes, Anopheles gambiae (Akron)en
dc.title.serialPLOS ONEen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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